ABSTRACT Pain is the primary reason why people seek medical care, with an estimated 116 million Americans suffering from chronic and poorly treated pain. Opioids and other drugs targeting the neuronal pathways of pain remain the gold standards today. However, it is now clear that neurons are not the only players that drive the establishment and maintenance of pain, and glial cells surrounding neurons are emerging as promising targets for the treatment of chronic pain. There is increasing evidence that satellite glial cells (SGCs) surrounding neurons in sensory ganglia modulate sensory processing and are particularly important for chronic pain. Our long-term goal is to have a better understanding SGCs, and leverage this knowledge to target specific glial signaling as a mean to identify new therapeutic strategies and reduce the use of opioids for the treatment of clinical pain. The objective of this application is to study and validate the tissue inhibitor of metalloproteinase 3 (TIMP3) signaling in SGCs as a novel therapeutic target for acute and chronic pain. TIMP3 has unique plethoric functions in inhibiting matrix metalloproteinases, the tumor necrosis factor-?-converting enzyme, and the vascular endothelial growth factor receptor 2. Because these enzymes and receptor have all been implicated in some extend in inflammation and pain, we hypothesize that the expression of the tissue inhibitor of metalloproteinase 3 (TIMP3) in SGCs is critical for the neuroimmune homeostasis in sensory ganglia, as well as for the development of pain. We propose to use multiple gain- and loss-of-function approaches in combination with a battery of behavioral, electrophysiological, and biochemical analyses to validate TIMP3 signaling for the treatment of acute and chronic pain. Specifically, we will test our hypothesis by the following specific aims: Aim 1 will establish the roles of TIMP3 signaling in pain and peripheral neuroimmune responses. Aim 2 will investigate and validate TIMP3 signaling in various animal models of acute and chronic pain. Aim 3 will investigate and test various drugs targeting TIMP3 signaling in human SGC cultures. Given the expression of TIMP3 in human SGCs and the strong validation of multiple small-molecules targeting TIMP3 signaling, including FDA-approved drugs, in various animal models of pain and in cultured human SGCs, we are confident that the successful completion of our research will have a rapid and positive impact on the millions of patients suffering of pain and at risk of opioid abuse.